The PI proposes to study the regulation of glucose metabolism during and after exercise using surgical and experimental tools that allow well-controlled experiments to be carried out in vivo. Experiments will be conducted in chronically catheterized postabsorptive dogs during rest, treadmill exercise and exercise recovery using surgical and pharmacological techniques to perturb or control the glucoregulatory system. Regulation of glucose fluxes and metabolism will be studied using isotopic (glucose, glucose analogs and gluconeogenic precursors) and arteriovenous difference (liver, kidney and gut) techniques. In addition, regulation of pancreatic hormone secretion and norepinephrine spillover will be measured using pancreatic arteriovenous differences. The specific aims of the proposed experiments are to determine: (a) the significance of peripheral vs portal vein hyperinsulinemia in suppression of endogenous glucose production during exercise; (b) the anatomical site that monitors the composition of the blood, allowing for fine control of blood glucose during rest and exercise; (c) whether exercise heightens the response to selective neuroglycopenia, such as it does the response to hypoglycemia; and (d) the means by which prior exercise enhances intestinal glucose absorption and the intrinsic ability of the liver to consume glucose. The common thread that links the proposed studies is the goal of comprehensively defining determinants of glucose availability in the presence of the increased metabolic challenges of muscular work. Accomplishing the objectives of the proposed experiments will add considerable insight into knowledge of glucoregulation during and after exercise in health and diabetes.